tbuckley/cabot-search huggingface dataset:
Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Joshua H. Choe, Tatsuya Kawase, An Xu, Asja Guzman, Aleksandar Z. Obradovic, Ana Maria Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M. Hwang, Joshua D. Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol Prives
Journal: Cancer Discovery (2023)

Abstract Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li–Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. Significance: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027
Which patients with melanoma are a priority for monitoring to detect new primary melanoma?
Authors: Aimilios Lallas
Journal: British Journal of Dermatology (2023)

Journal Article Which patients with melanoma are a priority for monitoring to detect new primary melanoma? Get access Aimilios Lallas Aimilios Lallas Conceptualization, Data curation, Writing - original draft First Department of Dermatology, School of Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece Email: alallas@auth.gr https://orcid.org/0000-0002-7193-0964 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 189, Issue 1, July 2023, Page e3, https://doi.org/10.1093/bjd/ljad125 Published: 17 April 2023 Article history Received: 12 April 2023 Accepted: 13 April 2023 Published: 17 April 2023 Corrected and typeset: 26 May 2023
Saliva and Plasma Antibody Levels in Children and Adolescents After Primary Infection With Omicron Variants of SARS-CoV-2 Infection in Germany
Authors: Constanze Heinzel, Yudi T. Pinilla, Ayla Binder, Peter G. Kremsner, Jana Held, Rolf Fendel, Andrea Kreidenweiss
Journal: JAMA Pediatrics (2023)

This cross-sectional study evaluates IgG antibody levels in children and adolescents in Germany following SARS-CoV-2 infection.
Immortal Time and Selection Biases in Study of Direct-Acting Antiviral Treatment and Hepatitis C Outcomes
Authors: Laurent Lam, Fabrice Carrat
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Immortal Time and Selection Biases in Study of Direct-Acting Antiviral Treatment and Hepatitis C Outcomes—Reply
Authors: Eiichi Ogawa, Yee Hui Yeo, Mindie H. Nguyen
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Conflicts of Interest Among Infectious Diseases Clinical Practice Guideline Authors and the Pharmaceutical Industry
Authors: Aileen S. Ahiskali, Dimitri M. Drekonja, Jonathan D. Alpern
Journal: JAMA Network Open (2023)

This cross-sectional study assesses the prevalence of conflicts of interest (COI) associated with guideline-recommended drugs among Infectious Diseases Society of America clinical practice guideline authors and compliance with the Council on Medical Specialty Societies and Institute of Medicine guidelines.
Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia
Authors: Andriana G. Kotini, Saul Carcamo, Nataly Cruz-Rodriguez, Malgorzata Olszewska, Tiansu Wang, Deniz Demircioglu, Chan-Jung Chang, Elsa Bernard, Mark P. Chao, Ravindra Majeti, Hanzhi Luo, Michael G. Kharas, Dan Hasson, Eirini P. Papapetrou
Journal: Blood Cancer Discovery (2023)

Abstract The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts. Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of a FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers. Significance: We report the generation of patient-derived iPSC models of all major genetic groups of human AML. These exhibit phenotypic hallmarks of AML in vitro and in vivo, inform the clonal hierarchy and clonal dynamics of human AML, and exhibit striking similarity to patient-matched primary leukemias upon xenotransplantation. See related commentary by Doulatov, p. 252. This article is highlighted in the In This Issue feature, p. 247
Epidermolysis bullosa: time to come together for better outcomes
Authors: Gabriela Petrof, Anna E Martinez
Journal: British Journal of Dermatology (2023)

Journal Article Epidermolysis bullosa: time to come together for better outcomes Get access Gabriela Petrof, Gabriela Petrof Conceptualization, Writing - original draft Department of Dermatology, Great Ormond Street Hospital, London, UK Correspondence: Gabriela Petrof. Email: gabriela.petrof@gosh.nhs.uk https://orcid.org/0000-0001-8113-0373 Search for other works by this author on: Oxford Academic Google Scholar Anna E Martinez Anna E Martinez Writing - review & editing Department of Dermatology, Great Ormond Street Hospital, London, UK Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 189, Issue 1, July 2023, Page 5, https://doi.org/10.1093/bjd/ljad123 Published: 17 April 2023 Article history Received: 11 April 2023 Published: 17 April 2023 Accepted: 03 May 2023 Corrected and typeset: 26 May 2023
Current and emerging approaches to noncompetitive AR inhibition
Authors: Christopher M. Riley, Jessica M. L. Elwood, Martyn C. Henry, Irene Hunter, J. Daniel Lopez‐Fernandez, Iain J. McEwan, Craig Jamieson
Journal: Medicinal Research Reviews (2023)

Abstract The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration‐resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand‐binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.
Comparison of Propylthiouracil vs Methimazole for Thyroid Storm in Critically Ill Patients
Authors: Sun Y. Lee, Katherine L. Modzelewski, Anica C. Law, Allan J. Walkey, Elizabeth N. Pearce, Nicholas A. Bosch
Journal: JAMA Network Open (2023)

Importance Thyroid storm is the most severe form of thyrotoxicosis, with high mortality, and is treated with propylthiouracil and methimazole. Some guidelines recommend propylthiouracil over methimazole, although the difference in outcomes associated with each treatment is unclear. Objective To compare outcomes associated with use of propylthiouracil vs methimazole for the treatment of thyroid storm. Design, Setting, and Participants This comparative effectiveness study comprised a large, multicenter, US-based cohort from the Premier Healthcare Database between January 1, 2016, and December 31, 2020. It included 1383 adult patients admitted to intensive or intermediate care units with a diagnosis of thyroid storm per International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and treated with either propylthiouracil or methimazole. Analyses were conducted from July 2022 to February 2023. Exposure Patients received either propylthiouracil or methimazole for treatment of thyroid storm. Exposure was assigned based on the initial thionamide administered. Main Outcomes and Measures The primary outcome was the adjusted risk difference of in-hospital death or discharge to hospice between patients treated with propylthiouracil and those treated with methimazole, assessed by targeted maximum likelihood estimation. Results A total of 1383 patients (656 [47.4%] treated with propylthiouracil; mean [SD] age, 45 [16] years; 473 women [72.1%]; and 727 [52.6%] treated with methimazole; mean [SD] age, 45 [16] years; 520 women [71.5%]) were included in the study. The standardized mean difference for age was 0.056, and the standardized mean difference for sex was 0.013. The primary composite outcome occurred in 7.4% of of patients (102 of 1383; 95% CI, 6.0%-8.8%). A total of 8.5% (56 of 656; 95% CI, 6.4%-10.7%) of patients who initiated propylthiouracil and 6.3% (46 of 727; 95% CI, 4.6%-8.1%) who initiated methimazole died in the hospital (adjusted risk difference, 0.6% [95% CI, −1.8% to 3.0%]; P = .64). There were no significant differences in duration of organ support, total hospitalization costs, or rates of adverse events between the 2 treatment groups. Conclusion and Relevance In this comparative effectiveness study of a multicenter cohort of adult patients with thyroid storm, no significant differences were found in mortality or adverse events in patients who were treated with propylthiouracil or methimazole. Thus, current guidelines recommending propylthiouracil over methimazole for treatment of thyroid storm may merit reevaluation.
Diagnostic value of reduced left atrial compliance during ergometry exercise in heart failure with preserved ejection fraction
Authors: Tomonari Harada, Kazuki Kagami, Takayuki Shina, Hidemi Sorimachi, Naoki Yuasa, Yuki Saito, Ayami Naito, Kuniko Yoshida, Toshimitsu Kato, Naoki Wada, Hideki Ishii, Masaru Obokata
Journal: European Journal of Heart Failure (2023)
Capacity for Regulation of Energy Intake in Infancy
Authors: Lyndsey A. F. Reynolds, Harlan McCaffery, Danielle Appugliese, Niko A. Kaciroti, Alison L. Miller, Katherine L. Rosenblum, Ashley N. Gearhardt, Julie C. Lumeng
Journal: JAMA Pediatrics (2023)

The capacity for regulation of energy intake (REI) to match energy needs is thought to contribute to differences in weight gain, and preventing excess infant weight gain is a priority.
Lactulose therapy for patients with cirrhosis, portal hypertension, and poor patient-reported outcomes: The Mi-Kristal trial
Authors: Elliot B. Tapper, Erin Ospina, Najat Salim, Xi Chen, Samantha Nikirk
Journal: Hepatology (2023)

Background and Aims: Poor patient-reported outcomes (PROs) are common in cirrhosis, including poor sleep and health-related quality of life (HRQOL). HE is a major driver of poor PROs. Many clinicians initiate lactulose therapy to address poor PROs. PRO-triggered therapy, however, has not been studied till date. Methods: We conducted a 28-day randomized trial of crystalline lactulose therapy (20 g BID) compared with no HE-directed therapy in 52 patients with cirrhosis, portal hypertension, no prior HE, and high Work Productivity and Activity Impairment scores (0–10) attributed to cirrhosis. The primary outcome was change in global HRQOL measured with Short Form-8 Health Survey. Secondary outcomes included change in Animal Naming Test score, Work Productivity and Activity Impairment, and sleep quality (scored “very bad” to “very good”). Approach and Results: Overall, 52 patients underwent randomization; 3 subjects withdrew from the crystalline lactulose arm (1 before medication initiation, 1 due to an unrelated condition, and 1 due to high baseline bowel movements). The average age was 60 years, the average Model for Endstage Liver Disease—Sodium score was 10.5, and 56% of the patients had ascites. Baseline bowel movements were 2.3/day, with 35% of the patients having Bristol Stool Scale &gt;4. At 28 days, there was no improvement in HRQOL: patients receiving crystalline lactulose had an 8.1-point (95% CI: 3.7–12.4) increase compared with 6.6 (95% CI: 2.3–10.8) in the control group ( p = 0.6). Lactulose was associated with a significantly ( p = 0.002) increased Animal Naming Test score (3.7, 95% CI: 2.1–5.4) versus the control group (0.2, 95% CI: −1.7, 1.4). Lactulose users reported more good sleep (92% vs. 52%, p = 0.001) and lower activity impairment (3.0 vs. 4.8, p = 0.02). Conclusions: Lactulose improves sleep and activity impairment in patients with poor PROs. We did not observe any improvement in global HRQOL after 28 days using the Short Form-8 Health Survey instrument.
Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders
Authors: Julie Werenberg Dreier, Marte-Helene Bjørk, Silje Alvestad, Mika Gissler, Jannicke Igland, Maarit K. Leinonen, Yuelian Sun, Helga Zoega, Jacqueline M. Cohen, Kari Furu, Torbjörn Tomson, Jakob Christensen
Journal: JAMA Neurology (2023)

Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied.
MicroRNA-216a is essential for cardiac angiogenesis
Authors: Rio P. Juni, Jordy M.M. Kocken, Ricardo C. Abreu, Lara Ottaviani, Tim Davalan, Burcu Duygu, Ella M. Poels, Aliaksei Vasilevich, Jana C. Hegenbarth, Mahesh Appari, Nicole Bitsch, Serve Olieslagers, Dorien M. Schrijvers, Monika Stoll, Joerg Heineke, Jan de Boer, Leon J. de Windt, Paula A. da Costa Martins
Journal: Molecular Therapy (2023)

While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress. While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.
The potential benefits of an automated flexible endoscope channel brushing system for manual cleaning of endoscopes
Authors: Koen van der Ploeg, Marco J. Bruno
Journal: Endoscopy (2023)

Contaminated endoscopes have resulted in numerous infectious outbreaks of multidrug-resistant microorganisms in past decades, including those with carbapenem-resistant Enterobacteriaceae [1]. Outbreaks are caused by failure to properly reprocess reusable endoscopes, leading to persistent endoscope contamination and patient exposure to potentially pathogenic microorganisms. Such outbreaks occurred even though no reprocessing lapses or endoscope defects were identified [1]. Despite numerous attempts to control the issue, to date patient-ready reusable duodenoscopes remain contaminated with gastrointestinal microflora in approximately 15 % of cases [2]. Moreover, endoscope contamination is not confined to the use of duodenoscopes. A recent review reported that 28 % of gastroscope channels and 32 % of colonoscope channels are contaminated after reprocessing [3].
Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial
Authors: Linda R Mileshkin, Kathleen N Moore, Elizabeth H Barnes, Val Gebski, Kailash Narayan, Madeleine T King, Nathan Bradshaw, Yeh Chen Lee, Katrina Diamante, Anthony W Fyles, William Small, David K Gaffney, Pearly Khaw, Susan Brooks, J Spencer Thompson, Warner K Huh, Cara A Mathews, Martin Buck, Aneta Suder, Thomas E Lad, Igor J Barani, Christine H Holschneider, Sylvia Van Dyk, Michael Quinn, Danny Rischin, Bradley J Monk, Martin R Stockler
Journal: The Lancet Oncology (2023)
Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma
Authors: Nicholas J. Vogelzang, James J. Rusthoven, James Symanowski, Claude Denham, E. Kaukel, Pierre Ruffie, Ulrich Gatzemeier, Michael Boyer, Salih Emri, Christian Manegold, Clet Niyikiza, Paolo Paoletti
Journal: Journal of Clinical Oncology (2023)

Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone.
ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors
Authors: Yeonsun Hong, Brandon L. Walling, Hye-Ran Kim, William S. Serratelli, John R. Lozada, Cooper J. Sailer, Andrea M. Amitrano, Kihong Lim, Raj Kumar Mongre, Kyun-Do Kim, Tara Capece, Elena B. Lomakina, Nicholas S. Reilly, Kevin Vo, Scott A. Gerber, Tan-Chi Fan, Alice Lin-Tsing Yu, Patrick W. Oakes, Richard E. Waugh, Chang-Duk Jun, Patrick M. Reagan, Minsoo Kim
Journal: Nature Immunology (2023)